Blood is sent out from the heart and passes through capillaries and veins after which it returns to the heart. Lymphatic vessels are vessels that form pathways for discharging tissue fluid separate from this circulation system. Lymphatic vessels maintain blood volume at a constant level and maintain a closed circulatory system by returning interstitial fluid, protein, fat, cells and the like that have leaked from blood vessels in peripheral tissues to the vascular system. In capillaries present in skin, the outsides of endothelial cells are surrounded by a basement membrane, and pericytes are further attached thereto. On the other hand, in lymphatic capillaries, there is hardly any basement membrane surrounding the outsides of endothelial cells and pericytes are not attached thereto. This structure is useful for efficiently incorporating body fluid and cells from the interstitium (Non-Patent Document 1). The tyrosinase-related receptor, vascular endothelial growth factor receptor 3 (VEGFR-3), has previously been shown to be specifically expressed in lymphatic endothelial cells, and its ligands in the form of VEGF-C and VEGF-D have been shown to induce lymphangiogenesis. In addition, VEGF-A has been clearly demonstrated to induce lymphangiogenesis mediated by VEGFR2 expressed in lymphatic endothelial cells (Non-Patent Document 2). Moreover, an example of a report describing lymph duct function is indicated below. Although prominent lymphangiogenesis was observed in mouse ear infected with adenovirus expressing VEGF-A, in addition to structural abnormalities, lymphatic vessel recovery function was clearly determined to be inhibited considerably based on the results of an experiment in which colloidal carbon was injected into the ear (Non-Patent Document 3). In other words, it is thought that lymphatic vessels are required to be suitably arranged and lined with lymphatic endothelial cells in order to function. We have defined this as “lymphatic vessel stabilization”.
Physical or chemical stimulation of skin induces vascular permeability due to angiogenesis, VEGF-A and the like, resulting in accumulation of tissue fluid and the occurrence of edema. On the other hand, these stimuli are also known to directly induce neogenesis and dilation of lymphatic vessels. Lymphatic vessel dilation has been observed to be induced by ultraviolet inflammation, while experiments involving injection of dye have clearly demonstrated that lymphatic vessel function is inhibited. Lymphatic vessels are thought to dilate in an attempt to recover interstitial fluid accompanying leakage of moisture into the dermis accompanying vasodilation. However, excessive lymphatic vessel dilation is also thought to delay edema by conversely lowering its recovery function (Non-Patent Document 4). In other words, “lymphatic vessel stabilization”, that does not induce excessive lymphatic vessel dilation is thought to be required for rapid recovery of interstitial fluid.
Examples of pathological states that have previously been known to involve lymphatic vessel dysfunction include congenital lymphedema as well as secondary lymphedema associated with filariasis, surgery, malignant tumors and inflammation. Examples of congenital lymphedema include Milroy's disease, Meige's disease and lymphedema-distichiasis syndrome. Lymphatic vessel aplasia or hypoplasia has been reported in Milroy's disease, while lymphatic vessel hyperplasia has been reported in lymphedema-distichiasis syndrome. On the basis of these findings as well, it is thought to be necessary to retain recovery function through not only lymphangiogenesis, but also lymphatic vessel stabilization (Non-Patent Document 5).